CMLTKIs – where are we up
to?
Steve O’BrienNorthern Institute for Cancer Research Newcastle University Medical
School
Newcastle, March 2013
Second generation TKIs are just better…
… no brainer?
Date of FDA approval First Line Second Line
1st 2nd
Imatinib 2002 2001 Gold standard No published experience
Dasatinib 2010 2006
Early data suggest a small advantage over
Imatinib
40-50% CCyR
Nilotinib 2010 2007
Early data suggest a small advantage over
Imatinib
40-50% CCyR
Bosutinib 2012
Not yet clear, maybe slightly
better than imatinib
40-50% CCyR
Ponatinib 2013? EPIC10-30% of
responses in 3rd line (T315I active)
TKIs in CML, the gold rush
Thanks to David Marin
2G drug trials
• DASISION, SPIRIT 2– Dasatinib
• ENESTnd– nilotinib
• BELA– Bosutinib
• EPIC– Ponatinib (3G??)
www.spirit-cml.org
www.spirit-cml.org
ENESTnd
• Primary endpoint: MMR at 12 months
• Key secondary endpoint: Durable MMR at 24 months
• Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on
study treatment, OS including follow-up
Imatinib 400 mg QD (n = 283)
Nilotinib 300 mg BID (n = 282)
* Nilotinib 400 mg BID (n = 281)• N = 846
• 217 centers
• 35 countries
Follow-up 5 years
Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design
• Primary endpoint: Confirmed CCyR by 12 months
• Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival
Follow-up
5 yearsRandomized*
Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259)• N=519
• 108 centers
• 26 countries
*Stratified by Hasford risk score
BELA Study Design
• Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome–positive (Ph+) CP CML 6 mo prior, no prior therapy other than hydroxyurea or anagrelide
• Primary endpoint: complete cytogenetic response (CCyR) at 12 months
• Key secondary and exploratory endpoints:– MMR at 12 months, time to and duration of CCyR and MMR, time to transformation to
AP/BP CML, event-free survival (EFS), and overall survival (OS)– Safety and tolerability
Phase 3 open-label trial in newly diagnosed CP CML
N = 502
139 sites
31 countries
Bosutinib 500 mg/day
n = 250
Imatinib 400 mg/day
n = 252
8-year follow-up
8-year follow-up
RANDOMIZE
1-year analysisRandomization is stratified based on Sokal risk score and geographical regions.
Nilotinib Leads to Faster / Deeper Responses
% M
MR
p<0.0001
p<0.0001
Dasatinib is Superior to Imatinib in CML-CP: MMR Rates
P<0.0001
MMR(%)
Mo 3 Mo 6 Mo 9 Mo 12 Any time
P<0.00003
ENESTnd DASISION
imatinib nilotinib difference imatinib dasatinib difference
CCyR at 12 month 65% 80% 15 73% 85% 12
CCyR at 24 month 77% 87% 10 82% 85% 3
PFS at 24 month 95.2% 98.0% 3 92.1% 93.7% 2
OS at 24 month 96.3 97.4% 1 95.2% 95.3% 0
Blue indicates a statistically significant differenceRed indicates a non significant difference
Early efficacy of nilotinib and dasatinib in comparison to imatinib
Saglio et al, NEJM 2010Kantarjian et al, NEJM 2010Kantarjian et al, Lancet Onc 2011Kantarjian et al, Blood 2012
First-Line Dasatinib is Associated with a Lower Rate of Progression to AP/BP
• No patient who achieved MMR progressed to accelerated or blast phase
• 2 patients who achieved CCyR progressed to accelerated or blast phase (1 with dasatinib, 1 with imatinib)
Progressedto AP/BP
(n)
3.5%
1.9%
Dasatinib 100 mg QD
Imatinib 400 mg QD
Reduced Overall Progression to AP/BC nu
mbe
r of p
atien
ts
• No patients who achieved MMR progressed to AP/BC• 3 patients who achieved CCyR on imatinib progressed to AP/BC
p=0.0095* p=0.0037*
*p-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC
0.7% 0.4%
3.9%
Side effects
PFS is similar in patients with CCyR regardless of depth of molecular response
Druker BJ, et al. NEJM, 2006;355(25):2408-17.
CML @ ASH
• ‘Even better’ responses– 2 possible strategies– Give more, give less!
• Stopping (reducing)– From CMR not MMR– 2nd gen data – early days
Imatinib vs ‘2nd gen’-inibCost
Duration of therapy
Imatinib
TKI2-inib
‘new-inib’
2015/16
Better/deeper responsePossible to stop
Shorter duration of therapyCheaper cost of treatment ‘package’?
More cost effective??
off patent
Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
2000 2010 20152005
Development License NICE approved
Off patent
??
??
TKIs in CML
(European license)
NICE
• TA251: first line treatment– 25 April 2012– Imatinib & nilotinib approved– Subject to Patient Access Scheme (PAS)– Dasatinib not approved (no PAS offered)
• TA 241: second line– 13 January 2012– Same as above
NICE
• Dasatinib– “People currently receiving dasatinib that is not
recommended according to 1.3 should be able to continue treatment until they and their clinician consider it appropriate to stop”
– Minimum free supply in SPIRIT 2 to 2018
– NICE rapid review currently in process
NICE• Bosutinib
– considered June 2013
– FAD approx Oct 2013
• Ponatinib
– no time frame as yet
So where are we now?
• Most CML patients are fine– There are more and more…
• Not much difference between TKIs?– Apart from cost and perhaps side effects– Use wisely/selectively– Imatinib off patent 2016
• We really need to figure out how to reduce and/or stop treatment for a lot more patients
ENESTnd study. Kantarjian et al. Lancet Oncology 2011: 12: 841
‘Isotypes’ of Otto Neurath and Gerd Arntz
Thanks to David Spiegelhalter
ENEST nd (nilotinib trial)Progression to AP/BC at 24 months
Kantarjian et al. Lancet Oncology 2011: 12: 841
Imatinib 4001 n=283: 12 events (4.2%) Nilotinib 3002 n=282: 2 events (0.7%)
ENEST nd (nilotinib trial)All deaths at 24 months
Kantarjian et al. Lancet Oncology 2011: 12: 841
Imatinib 4001 n=283: 11 events (3.8%) Nilotinib 3002 n=282: 9 events (3.2%)
How many patients with CML?
£290Mper year
£464Mper year
£????
Huang et al. Cancer 2011: doi: 10.1002/cncr.26679USA: 311, 591,917UK: 62,218,761USA: 311, 591,917UK: 62,218,761
NHS spending on CML
• In next 10 years…• Between £290M - £460M per annum• Over next ten years…
£2-3 billion?
Difficult times…
So can we afford all these great new developments in CML?
Second generation TKIs are just better…
… no brainer?
Will there be any more???
• Kinase inhibitors– Imatinib & others
• ABL, CML– Sunitinib
• PDGF-R, VEGF-R, renal– Afatinib
• Her2, EGF-R, breast cancer– Regorafenib– Trametinib– Dabrafenib– Ibrutinib– Vemurafenib
• B-RAF, melanoma, hairy cell leukaemia– Ruxolitinib JAK-2
• Targeted antibodies– Trastuzumab (Herceptin)
• HER2/neu receptor, breast cancer– Rituximab (Rituxan)
• CD20, lymphoid disease– Cetuximab (Erbitux)
• EGF-R, colorectal– Bevacizumab (Avastin)
• VEGF, various
Modern medicines – amazing!
So what about generics?
2016 in UK
CML @ ASH
• Drugs jostling for position– Imatinib off patent in 2016– At least 10 generics waiting in the wings
• Genfatinib, Imatinib Teva, Veenat, Celonib, Imatib, Mesylonib, Mitinab, Shantinib, Zoleta, Spotnib.
– Dasatinib, nilotinib (radotinib), bosutinib, ponatinib
• Better responses
– No difference in survival
So what about generics?
2016 in UK
CMLTKIs – where are we up
to?
Steve O’BrienNorthern Institute for Cancer Research Newcastle University Medical
School
Newcastle, March 2013